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Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy

Author

Listed:
  • Stacy A. Hussong

    (University of Oklahoma Health Sciences Center
    University of Oklahoma Health Sciences Center
    Oklahoma City Veterans Health Care System)

  • Andy Q. Banh

    (University of Texas Health San Antonio
    University of Texas Health San Antonio)

  • Candice E. Skike

    (University of Texas Health San Antonio)

  • Angela O. Dorigatti

    (University of Texas Health San Antonio)

  • Stephen F. Hernandez

    (University of Texas Health San Antonio)

  • Matthew J. Hart

    (University of Oklahoma Health Sciences Center
    University of Oklahoma Health Sciences Center
    University of Oklahoma Health Sciences Center)

  • Beatriz Ferran

    (University of Oklahoma Health Sciences Center
    University of Oklahoma Health Sciences Center)

  • Haneen Makhlouf

    (University of Oklahoma Health Sciences Center
    University of Oklahoma Health Sciences Center)

  • Maria Gaczynska

    (University of Texas Health San Antonio
    University of Texas Health Science Center at San Antonio)

  • Pawel A. Osmulski

    (University of Texas Health San Antonio
    University of Texas Health Science Center at San Antonio)

  • Salome A. McAllen

    (University of Texas Medical Branch at Galveston
    University of Texas Medical Branch at Galveston
    University of Texas Medical Branch at Galveston)

  • Kelly T. Dineley

    (University of Texas Medical Branch at Galveston
    University of Texas Medical Branch at Galveston
    University of Texas Medical Branch at Galveston)

  • Zoltan Ungvari

    (University of Oklahoma Health Sciences Center
    University of Oklahoma Health Sciences Center
    Semmelweis University)

  • Viviana I. Perez

    (Hevolution Foundation, 5.08)

  • Rakez Kayed

    (University of Texas Medical Branch at Galveston
    University of Texas Medical Branch at Galveston
    University of Texas Medical Branch at Galveston)

  • Veronica Galvan

    (University of Oklahoma Health Sciences Center
    University of Oklahoma Health Sciences Center
    Oklahoma City Veterans Health Care System)

Abstract

Vascular mechanisms of Alzheimer’s disease (AD) may constitute a therapeutically addressable biological pathway underlying dementia. We previously demonstrated that soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, including prominently in microvascular endothelial cells. Here we show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy and drives AD-like brain microvascular deficits. Microvascular impairments in P301S(PS19) mice were partially negated by selective removal of pathogenic soluble tau aggregates from brain. We found that similar to trans-neuronal transmission of pathogenic forms of tau, soluble tau aggregates are internalized by brain microvascular endothelial cells in a heparin-sensitive manner and induce microtubule destabilization, block endothelial nitric oxide synthase (eNOS) activation, and potently induce endothelial cell senescence that was recapitulated in vivo in microvasculature of P301S(PS19) mice. Our studies suggest that soluble pathogenic tau aggregates mediate AD-like brain microvascular deficits in a mouse model of tauopathy, which may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of soluble tau aggregates.

Suggested Citation

  • Stacy A. Hussong & Andy Q. Banh & Candice E. Skike & Angela O. Dorigatti & Stephen F. Hernandez & Matthew J. Hart & Beatriz Ferran & Haneen Makhlouf & Maria Gaczynska & Pawel A. Osmulski & Salome A. M, 2023. "Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37840-y
    DOI: 10.1038/s41467-023-37840-y
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    References listed on IDEAS

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    1. Mauro Montalbano & Salome McAllen & Nicha Puangmalai & Urmi Sengupta & Nemil Bhatt & Omar D. Johnson & Michael G. Kharas & Rakez Kayed, 2020. "RNA-binding proteins Musashi and tau soluble aggregates initiate nuclear dysfunction," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    2. Jean-Philippe Coppé & Christopher K Patil & Francis Rodier & Yu Sun & Denise P Muñoz & Joshua Goldstein & Peter S Nelson & Pierre-Yves Desprez & Judith Campisi, 2008. "Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor," PLOS Biology, Public Library of Science, vol. 6(12), pages 1-1, December.
    3. Y. Iturria-Medina & R. C. Sotero & P. J. Toussaint & J. M. Mateos-Pérez & A. C. Evans, 2016. "Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    4. Mathias Jucker & Lary C. Walker, 2013. "Self-propagation of pathogenic protein aggregates in neurodegenerative diseases," Nature, Nature, vol. 501(7465), pages 45-51, September.
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